Observational Study Medicine ®

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Ophthalmic manifestations in
IgG4-related disease
Clinical presentation and response to treatment
in a French case-series
Mikael Ebbo, MDa, Matthieu Patient, MDa, Aurelie Grados, MDa, Matthieu Groh, MDb, Julien Desblaches, MDc,
Eric Hachulla, MD, PhDd, David Saadoun, MD, PhDe, Sylvain Audia, MD, PhDf, Aude Rigolet, MDe,
Benjamin Terrier, MD, PhDb, Antoinette Perlat, MDg, Constance Guillaud, MDh, Frederic Renou, MDi,
Emmanuelle Bernit, MDa, Nathalie Costedoat-Chalumeau, MD, PhDb, Jean-Robert Harlé, MDa,
∗
Nicolas Schleinitz, MDa,
Downloaded from https://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3dNjRBBAKGOCr/LStAao1A+wAjP3Bi9yHEP15XgfUzOY= on 12/27/2018

Abstract
IgG4-related disease (IgG4-RD) is characterized by variable tissue or organ involvements sharing common pathological findings.
Orbital or orbital adnexa involvement of the disease has been reported in a few case series. The aim of our study was to characterize
and analyze ophthalmic manifestations from a nationwide French case-series.
Patients with IgG4-RD and orbital or orbital adnexa involvement included in the French multicentric IgG4-RD case-registry were
identified. Only patients fulfilling “modified” comprehensive diagnostic criteria with pathological documentation were retained for the
study. Clinical, biological, pathological, radiological findings and data regarding the response to treatment were retrospectively analyzed.
According to our data registry, the frequency of IgG4-related ophthalmic disease (IgG4-ROD) was 17%. Mean age at diagnosis was
55.1 ± 7.1 years with a male/female ratio of 2.2. The 19 cases of IgG4-ROD consisted of lacrimal gland (68.4%), soft tissue (57.9%), extra-
ocular muscles (36.8%), palpebral (21.1%), optical nerve (10.5%), orbital bone (10.5%), and mononeuritis (V1 and/or V2, 10.5%)
involvements. IgG4-ROD was bilateral in 57.9% of cases. Extra-ophthalmic manifestations were reported in 78.9% of cases. All patients
responded to prednisone but two-thirds of patients relapsed within a mean (SD) of 9.8 (3.5) months and 72.2% required long-term
glucocorticoids and/or immunosuppressive agents. Eight patients were treated by rituximab with a favorable response in 87.5% of cases.
Lacrimal involvement is the most frequent ophthalmic manifestation of IgG4-RD and is frequently associated with extra-orbital
manifestations. Despite initial favorable response to steroids, the long-term management of relapsing patients needs to be improved.
Abbreviations: 18F-FDG PET/CT = 18F-fluorodeoxyglucose positron emission tomography/computed tomography, AIP =
autoimmune pancreatitis, ANA = antinuclear antibodies, AZA = azathioprine, CDC = Comprehensive Diagnostic Criteria, CRP = C-
reactive protein, DMARDs = disease-modifying antirheumatic drugs, dsDNA = double-stranded DNA, EOM = extra-orbital muscle,
HPF = high-power field, IgG4-RD = IgG4-related disease, IgG4-ROD = IgG4-related ophthalmic disease, IOI = idiopathic orbital
inflammation, LG = lacrimal gland, LN = lymph nodes, MMF = mycophenolate mofetil, MTX = methotrexate, pIgG4+ = IgG4+ plasma
cells, RTX = rituximab, SD = standard deviation, sIgG4 = serum IgG4.
Keywords: IgG4-related dacryoadenitis, IgG4-related disease, IgG4-related ophthalmic disease, orbital inflammatory pseudo-
tumor, rituximab

Editor: Jesper Kers.

The authors have no conflicts of interest to disclose.
Supplemental Digital Content is available for this article.
a
Médecine Interne, Groupe Hospitalier Timone, AP-HM, Aix-Marseille Université,
Marseille, b Médecine Interne, Hopital Cochin, Université Paris-Descartes, Paris,
c
Médecine Interne, Centre hospitalier de Pau, Pau, d CHRU—Hôpital Claude
Huriez, Université de Lille, Lille, e Médecine Interne, Groupe hospitalier Pitie
Salpêtrière AP-HP, Université Pierre et Marie Curie, Paris, f Médecine interne,
CHU le Bocage, Université de Bourgogne, Dijon, g Médecine Interne, CHU
Rennes, Rennes, h Médecine interne, CHU Mondor, Créteil, i CHG Saint Denis de
la Réunion, Réunion, France.
∗
Correspondence: Nicolas Schleinitz, Department of Internal Medicine, Groupe
Hospitalier Timone, AP-HM, Aix-Marseille Université, Marseille, 13385, cedex 5,
France (e-mail: nicolas.schleinitz@ap-hm.fr).
Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others
to remix, tweak, and build upon the work non-commercially, as long as the author
is credited and the new creations are licensed under the identical terms.
Medicine (2017) 96:10(e6205)
Received: 14 October 2016 / Received in final form: 29 December 2016 /
Accepted: 6 February 2017
http://dx.doi.org/10.1097/MD.0000000000006205
1. Introduction
IgG4-related disease (IgG4-RD) is characterized by typical mass
forming lesions with pathological analysis showing dense
lymphoplasmacytic infiltrates, fibrosis, and numerous IgG4+
plasmocytes.[1] The most frequent manifestations are type 1
autoimmune pancreatitis (AIP), salivary gland and lacrimal gland
(LG) involvements, sclerosing cholangitis, tubulo-interstitial
nephritis, lymph nodes (LN) enlargement, and retroperitoneal
fibrosis.[2–4] Several other tissues or organs can be affected by the
disease. These manifestations can be localized to a single organ or
affect several organs either at the same time or metachronously.[5]
Specific orbital and orbital adnexa involvement have previously
been reported from case-series of IgG4-RD patients or from the
retrospective analysis of pathological material obtained from
orbital pseudo-inflammatory tumor or idiopathic orbital inflam-
mation (IOI) biopsies. These studies have shown that IgG4-
related ophthalmic disease (IgG4-ROD) includes several inflam-
matory conditions of the orbit and the ocular adnexa.[6]
Dacryoadenitis, sometimes in the setting of the Mikulicz
syndrome, is frequent but IgG4-ROD may also involve orbital

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Ebbo et al. Medicine (2017) 96:10
soft tissues, extra-ocular muscles, eyelids, optical and trigeminal
nerves, orbital bones, and the sclera.[6] Hence, differential
diagnoses are numerous and include primary Sjögren syndrome,
lymphoma, sarcoidosis, granulomatosis with polyangiitis, xan-
thogranuloma, Erdheim-Chester and Rosai-Dorfman dis-
eases.[7,8] Because serum IgG4 (sIgG4) elevation and IgG4+
plasma cells tissue infiltration are not specific of IgG4-RD, such
diagnosis should only be retained after that an extensive
diagnostic workup (including a complete clinical, biological,
radiological, and pathological confrontation) has ruled out
alternate diagnoses.[9–11]
In large series, lacrimal gland (dacryoadenitis) involvement
varies from 22% to 50%[4,12,13] and orbital involvement from
4% to 22%.[3,4,13] Retrospective analysis of pathological
specimen from benign lymphoproliferative disorders and orbital
inflammation have reported specific characteristics of IgG4-RD
in up to 40% of cases.[14,15] Such discrepancies between studies in
the rates of IgG4-R0D can, at least partly, be explained by the
differences of disease criteria retained for tissue IgG4+ plasma
cells infiltrates (i.e., either > 10/high power field (HPF),[7] > 30/
HPF[16] or > 50–100/HPF[11] with an IgG4+/IgG+ ratio >40%).
One hundred seventy-two pooled cases of IgG4-ROD from case-
series or case reports have been recently analyzed in a review. The
great majority of patients were from Asia or North America.[6]
Larger series are needed to better characterize this rare condition
and to improve patient care. Here, we report on the clinical,
biological, and pathological characteristics and the response to
treatment from 19 patients with IgG4-ROD from a nationwide
French case-registry.
2. Patients and methods
The French multicentric case database for IgG4-RD (n = 147) was
used to select patients presenting with ophthalmic manifestations.
Patients were included between 2009 and 2016 and their data
were recorded retrospectively from each center. All patients
fulfilled the IgG4-RD “modified” comprehensive diagnostic
criteria,[7] defined by in all patients: clinical or radiological
diffuse/localized swelling or masses in characteristic single or
multiple organs; in possible and definite cases: elevated serum
IgG4 levels (>1.35 g/L); in probable and definite cases: lympho-
plasmacytic polyclonal infiltrate, fibrosis, obliterative phlebitis,
and/or increased numbers of eosinophils, with either a ratio of
IgG4+/IgG+ (or IgG4+/CD138+) cells >40% or >10 IgG4+
plasma cells/HPF (supplemental Table 1, http://links.lww.com/
MD/B594). Immunostaining criterion n°3 was modified from the
original pathological statement[7] since in our retrospective and
multicentric study some tissue biopsies were performed before the
latter publication was released and these 2 criteria were not
systematically reported in the pathological reports. Patients who
did not meet concomitantly both criteria had missing data (IgG-
immunostaining or strict count/HPF) but had neither a ratio of
IgG4+/IgG+ plasma cells <40% nor a number of IgG4+ plasma
cells/HPF < 10. In several cases the ratio was not analyzed
because IgG-immunostaining suffered from high background
staining. In all cases a stringent clinicopathologic confrontation
was performed in order to rule out all potential alternate
diagnoses (especially those in which positive IgG4+ plasma cell
infiltrates have been described).[8,11]
For all cases, the diagnosis of IgG4-RD was retained by the
treating physician based on clinical, biological, radiological, and
pathological findings. Patients were defined as having IgG4-ROD
when they had ≥1 ophthalmic manifestation(s) and above-
2
Medicine
mentioned histological criteria for IgG4-RD in either orbital,
periorbital or extra-orbital tissues (supplemental Table 1, http://
links.lww.com/MD/B594). Ophthalmic manifestations were
defined as lacrimal gland (LG), soft tissue, extra-orbital muscle
(EOM), eyelid, cranial nerve, and/or contiguous bone involve-
ments. The detection of LN by either clinical, radiological or
18
F-FDG PET/CT was considered an IgG4-RD involvement in the
absence of another obvious cause.
When evaluable, response to treatment was retrospectively
analyzed based on the clinical, biological, and radiological
evaluations performed during follow-up. Complete response
was defined by a total improvement, partial response by
an incomplete improvement and nonresponse by the absence
of any improvement or by worsening. Biological response
was based on normalization of sIgG4 titers. Values are given
as mean ± SD.
According to the current French Legislation (Loi Huriet-
Sérusclat 88-1138, December 20, 1988, and its subsequent
amendments, text available at http://www.chu-toulouse.fr/IMG/
pdf/loihuriet.pdf), an observational study that does not change
routine management of patients does not need to be declared or
submitted to the opinion of a research ethics board.
3. Results
3.1. General characteristics
Twenty-five patients from the French case registry for IgG4-RD
presented with ophthalmic manifestations. Hence, the overall
estimated prevalence of IgG4-ROD in patients with IgG4-RD
was 17%. Six patients were excluded due to insufficient data or
the absence of sufficient pathological documentation and 19
patients (13 males and 6 females) with a mean age at diagnosis of
55.1 ± 7.1 years (range: 22–86 years) were retained in the final
analysis (Table 1). Females with IgG4-ROD (mean age:
48.5 years) were younger than males (56.7 years).
All patients fulfilled the definition of either definite or probable
IgG4-RD according to the “modified” comprehensive diagnostic
criteria (supplemental Table 1, http://links.lww.com/MD/B594).
Among 18 patients with available serum IgG4 values, 11 patients
(61.1%) presented a definite diagnosis, 7 patients (38.9%) a
probable diagnosis.
3.2. Clinical characteristics
IgG4-ROD consisted of LG (68.4%), soft tissue (57.9%), extra-
ocular muscles (EOM, 36.8%), palpebral (21.1%), optical nerve
(10.5%), orbital bone (10.5%), and mononeuritis (V1 and/or
V2, 10.5%) involvements (Table 1). In addition, disease-specific
keratitis was reported in a single patient. Overall, IgG4-RD’s
extra-ophthalmic manifestations were reported in 78.9% of cases
and consisted of pancreatic (n = 7), salivary gland (n = 11),
retroperitoneal (n = 2), biliary tract (n = 1), LN (n = 13), sinus (n =
3), renal (n = 3), pulmonary (n = 2), prostatic (n = 1), testicular
(n = 1), hypophyseal (n = 1), thyroid (n = 1), and paravertebral
(n = 1) involvements. In 6 of 15 IgG4-ROD patients, extra-
ophthalmic manifestations were restricted to the head and neck
area: salivary gland ± LN (n = 4), sinus (n = 1), Riedel thyroiditis
(n = 1). Lacrimal gland involvement was associated with other
features of IgG4-ROD including 61.5% (8/13) of cases with soft
tissue (n = 5), palpebral (n = 4), EOM (n = 3), optical nerve (n = 1),
and V2 (n = 1) involvements. All 13 patients with LG involvement
presented with extra-ophthalmic features of IgG4-RD.
Ebbo et al. Medicine (2017) 96:10 www.md-journal.com

Table 1
Clinical characteristics of 19 patients with IgG4-ROD.
Case Age/ gender Orbital manifestations Extra-orbital manifestations Bilateral VAI Serum IgG4 (g/L)
1 58/F Lacrimal gland, eyelid RPF, AIP, salivary gland, sclerosing Yes No 0.3
cholangitis, LN
2 68/M EOM, soft tissue, optical nerve, orbital bone None No Yes 1.031
3 86/M Lacrimal gland, soft tissue Salivary gland, LN No No 0.153
4 32/F Lacrimal gland, soft tissue, palpebral, EOM LN Yes No 4.01
5 63/M Lacrimal gland AIP, Salivary gland, LN Yes No 2.9
6 61/M Soft tissue Salivary gland Yes No 0.32
7 53/M Lacrimal gland AIP, salivary gland, TIN, LN No No 0.133
8 61/F Soft tissue, EOM, V1 and V2 none No No 7.3
9 35/M Lacrimal gland TIN, prostate, testis, lung, AIP, LN Yes No 18.5
10 22/M Lacrimal gland, EOM, eyelid Sinus, AIP, salivary gland, TIN, LN, lung Yes No 3
11 38/F Soft tissue, EOM None No No 1.04
12 42/M Soft tissue None No Yes ND
13 65/M Soft tissue, EOM, orbital bone Sinus No No ND
14 62/M Lacrimal gland AIP, salivary gland, LN, sinus No No 12.3
15 67/M Lacrimal gland, soft tissue Riedel thyroiditis, LN Yes No 5.2
16 70/F Lacrimal gland, eyelid Salivary gland, LN, prevertebral infiltration, RPF Yes No >5
17 61/F Lacrimal gland, soft tissue, optic nerve AIP, salivary gland, hypophysitis, LN Yes Yes 28.7
18 54/M Lacrimal gland, soft tissue, EOM, V2 Salivary gland, LN Yes Yes 12.25
19 48/M Lacrimal gland Salivary gland, LN Yes No 8.78
AIP = autoimmune pancreatitis, EOM = extra-orbital muscle, F = female, LN = lymph node, M = male, RPF = retro-peritoneal fibrosis, TIN = tubulo-interstitial nephritis, VAI = visual acuity impairment.

IgG4-ROD was bilateral in 11 cases (57.9%) among which 10
patients (90.9%) presented with dacryoadenitis (LG) and the
remaining patient presented with bilateral soft tissue involve-
ment. Of note, all patients with bilateral IgG4-ROD presented
with extra-orbital manifestations, with disease symptoms
restricted to the head and neck area in 27.7%. Unilateral
involvement was reported in 8 cases (42.1%) and was not
restricted to a specific localization of IgG4-ROD. The rates of
unilateral involvement according to each subtype of IgG4-ROD
manifestations were: 23.1% in LG, 54.5% in soft tissue, 57.1%
in EOM, 50% in optical nerve, 50% in trigeminal V1/V2 nerve,
and 100% (2/2) in orbital bone involvements.
IgG4-ROD was associated with visual acuity impairment or
loss of vision in 4 patients. All of the latter patients presented with
soft tissue involvement and 2 had bilateral IgG4-ROD. In 1
patient (patient 12), orbital soft tissue involvement was isolated
with no other IgG4-ROD or extra-orbital IgG4-RD manifesta-
tion. In the 3 other patients, soft tissue involvement was
associated with neural (optical nerve in 2, V2 in 1) and EOM
involvements (2/3).
3.3. Pathological findings
Pathological analysis of IgG4-ROD involvement was available in
10 cases: soft tissue in 8/11 and LG in the remaining 2 patients
(Table 2). A dense lymphoplasmacytic infiltrate was the main
feature reported in all cases, while fibrosis was found in 8 of 10
biopsies and eosinophilic infiltrates in 3 of 10. Obliterative
phlebitis was never reported and a storiform pattern was not
mentioned in the only available lacrimal specimen with fibrosis.
Immunohistochemistry for IgG4-positive plasma cells was
performed in 9 of 10 cases showing either an IgG4+/IgG+
plasma cells ratio >40% (n = 5) or a IgG4+ plasma cells count/
HPF >10 (n = 7) (Table 2). In the patient without available data
regarding IgG4 immunostaining on orbital tissue (patient 17), the
pathological assessment of IgG4-RD was performed on a
pancreas biopsy showing a IgG4+/IgG+ cells ratio of 50% with
45 IgG4+ plasma cells (pIgG4+)/HPF. In patients without
pathological documentation of IgG4-ROD, pathological exami-
nation and IgG4 immunostainings were assessed in pancreas
biopsy for patients 1 (>10 pIgG4+/HPF) and 5 (>50 pIgG4+/
HPF); in salivary gland biopsies for patients 3 (ratio >40% and

Table 2
Pathological characteristics of orbital biopsies in patients with IgG4-ROD.
Case Biopsy site Fibrosis LP Eo Obliterative phlebitis IgG4+/IgG+ ratio IgG4+ /HPF “Modified” CDC category
2 Soft tissue + + >50% >50 Probable
4 LG + + ND >100 Definite
8 Soft tissue + + + 90% NA Definite
11 Soft tissue + + + ND >10 Probable
12 Soft tissue + + ND >40 Probable
13 Soft tissue + + >50% >50 NE
14 LG + 50% NA Definite
15 Soft tissue + ND >30 Definite
∗
17 Soft tissue + + ND ND Definite
18 Soft tissue + + + 50% 25 Definite
CDC = comprehensive diagnostic criteria, Eo = eosinophils, HPF = high-power field, LG = lacrimal gland, LP = dense lymphoplasmocytic infiltrate, NE = nonevaluable (nonavailable serum IgG4).
∗
For patient 17, pathological assessment of IgG4-RD was performed in a pancreas biopsy with a 50% IgG4+/IgG+ cells ratio and 45 IgG4+ plasma cells/HPF.

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Ebbo et al. Medicine (2017) 96:10 Medicine

>50 pIgG4+/HPF), 7 (100 pIgG4+/HPF), and 16 (ratio 50% and
30 pIgG4+/HPF); in kidney biopsies for patients 7 (ratio > 40%
and 115 pIgG4+/HPF) and 9 (ratio >50% and 30 pIgG4+/HPF);
in LN biopsies for patients 10 (ratio > 90%) and 19 (ratio >40%
and >10 pIgG4+/HPF, the parotid biopsy otherwise showing only
fibrosis without cell infiltrates). The latter 2 patients with only LN
pathological analysis presented with other typical manifestations
of IgG4-RD and high levels of sIgG4.
3.4. Biological findings
Serum IgG4 (sIgG4) levels were elevated (>1.35 g/L) in 11 of 18
(61.1%) patients with available sIgG4 titers. Mean sIgG4 was
6.52 g/L ± 6.00 (range: 0.1–28.7 g/L). CRP levels were variable
but usually moderately elevated, with a mean value of 16.7 mg/L
± 0.7 (range: 1–119 mg/L). Antinuclear autoantibodies were
found in 7 of 17 patients, between 1/80 and 1/320 but no patient
had either dsDNA or extractable nuclear antigen (especially SSA
or SSB) positive autoantibodies (Supplemental Table 2, http://
links.lww.com/MD/B594).
3.5. Response to treatment
All patients received first-line therapy with prednisone. Twelve
patients received prednisone for orbital manifestations and in the
remaining cases, the treatment was initiated for other IgG4-RD
localizations (Table 3). Overall 13 of 19 patients (68.4%)
relapsed after a first course of glucocorticoids. Relapses were
treated by azathioprine (AZA, n = 6), methotrexate (MTX, n = 1),
mycophenolate mofetil (MMF, n = 2), and rituximab (RTX, n =
8) (Table 3). At last follow-up, 72.2% of patients remained under
treatment with either prednisone alone (n = 11), MMF (n = 1), or
both (n = 1). Mean follow-up was 40.2 ± 79.2 months (range:
3–115 months). Treatment with rituximab was associated with
complete clinical and complete or partial radiological responses
in all patients but one (otherwise considered a nonresponder due
to clinical and radiological findings).
Among the 12 patients treated for IgG4-ROD, the clinical
response to prednisone was reported in all patients and a
biological response (normalization of sIgG4 levels) was found in
5 of 6 evaluable patients (1 nonresponder and 6 patients with

Table 3
Treatment and treatment responses in 19 patients with IgG4-ROD.
Treatment indication TT Response to TT Relapse TT at last visit FwuP (m)
1 AIP, RPF PDN Clin: R; Bio: R; IM: R Yes PDN 5 mg/d 115
AZA Clin: NR
2 IgG4-ROD PDN Clin: R; Bio: R; IM: CR Yes PDN 4 mg/d 29
RTX Clin: R; Bio: NE; IM: PR
3 IgG4-ROD PDN Clin: R; Bio: NR; IM: CR No PDN 7 mg/d 7
4 IgG4-ROD PDN Clin: R; Bio: R; IM: NA Yes PDN 10 mg/d 17
5 AIP PDN Clin: R; Bio: R; IM: R No PDN 10 mg/d 7
6 IgG4-ROD PDN Clin: R; Bio NA; IM: NA Yes PDN 10 mg/d 23
RTX Clin: R; Bio: R; IM: NA
7 AIP, TIN PDN Clin: R; Bio: R; IM: R Yes PDN 7.5 mg/d 47
RTX Clin: R; Bio: R; IM: NA
8 IgG4-ROD PDN Clin: R; Bio: R; IM: PR Yes PDN 5 mg/d 112
AZA NR
RTX Clin: R; Bio: NE; IM: R
9 AIP, TIN PDN Clin: R; Bio: R; IM: R Yes 0 40
AZA NR
RTX Clin: R; Bio: R; IM: R
10 AIP, TIN PDN Clin: R; Bio: R; IM: R Yes PDN 5 mg/d 52
MTX
11 IgG4-ROD PDN Clin: R; Bio: NE; IM: PR No 0 19
RTX Clin: NE; Bio: NE; IM:NE
12 IgG4-ROD PDN Clin: R; Bio: NE; IM: PR Yes PDN 10 mg/d 51
RTX Clin: R; Bio: NE; IM: PR
13 IgG4-ROD PDN Clin: R; Bio: R; IM: R Yes MMF 32
AZA Toxicity
RTX Clin: NR; Bio: PR; IM:NR
14 AIP PDN Clin: R; Bio: R; IM: NA Yes PDN 5 mg/d 14
15 IgG4-ROD PDN Clin: R; Bio: NE; IM: NE No 11
16 RPF PDN Clin: R; Bio: R; IM: R Yes PDN 10 mg/d + MMF 60
AZA Toxicity
MMF Clin: R; Bio: PR; IM: PR
∗
17 AIP and IgG4-ROD PDN Clin: R; Bio: R; IM: NA No NE 75
18 IgG4-ROD PDN Clin: R; Bio: R; IM: PR Yes 0 50
AZA Toxicity
MMF Toxicity
RTX Clin: R; Bio: R; IM:PR
19 IgG4-ROD PDN Clin: R; Bio: PR; IM: NE No 0 3
For each line of treatment (column 3) responses to treatment for clinical (Clin), biological (Bio), and imagery (IM) are detailed in column 4. When the treatment was stopped for side effects “toxicity” is noted in
column 4.
AIP = autoimmune pancreatitis, AZA = azathioprine, Bio = biological, Clin = clinical, FuP = follow-up, IgG4-ROD = IgG4-related ophthalmic disease, IM = imagery, MMF = mycophenolate mofetil, NE = not
evaluable, NR = nonresponder, PDN = prednisone, PR = partial response, R = response, RPF = retroperitoneal fibrosis, RTX = rituximab, TIN = tubulointerstitial nephritis, TT = treatment.
∗
Patient deceased at 75 months follow-up by an unrelated cause.

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Ebbo et al. Medicine (2017) 96:10
normal baseline sIgG4 levels in remaining cases). A radiological
response was reported in all 6 evaluable patients (complete
response, n = 2; partial response, n = 4). Five patients initially
treated for IgG4-ROD required no other treatment. Seven
patients (58.3%) relapsed with a mean time to first relapse of 9.8
± 3.5 months (range: 6–15), and received as second-line therapy
AZA in 3 and RTX in 7.
4. Discussion
IgG4-ROD has recently been recognized as a cause of idiopathic
orbital inflammation (IOI) or orbital benign lymphoproliferative
disease.[6,14,16,17] IgG4-ROD was first identified thanks to the
reporting of patients with orbital manifestations concomitant to
other IgG4-RD manifestations and to the retrospective search of
IgG4-RD pathological characteristics in pathological specimen of
inflammatory orbital diseases. The frequency of IgG4-ROD
ranges 4% to 34% of IgG4-RD patients according to the largest
case series published to date.[17–20] Our findings are in line with
these data since 17% of all patients included in the French case
registry for IgG4-RD presented with symptoms likely to be
related to IgG4-ROD. Besides, clinical manifestations in our case
series are comparable to those reported in North American or
Japanese patients.[6] Mean age was similar to previous reports
but we found a relatively higher male/female ratio of 2.2.[6]
Concordant with previous series, IgG4-ROD was bilateral in
58% of the patients and was associated with extra-orbital
manifestations in around 80% of cases (70%–100%).[6,17] Next,
LG was the most frequent organ involved, followed by soft tissue
and EOM. Because radiological findings were not systematically
reviewed, we could not assess the true prevalence of trigeminal
nerve enlargement otherwise considered by others as useful to
differentiate IgG4-ROD with other inflammatory orbital dis-
eases.[6,21,22] Of note, we report on 2 patients with clinical
involvement of the trigeminal nerve and 2 with optical nerve
involvement. Bone involvement was also found in 2 additional
cases. One patient presented with sclera/keratitis involvement,
but none had conjunctival or lacrimal sac involvements. Contrary
to previous reports suggesting that uveitis might belong to the
spectrum of IgG4-ROD,[23] we did not identify such case in the
present study.
Visual impairment has been reported in as high as 40% of
patients with IgG4-ROD presenting as IOI.[24] In 4 (21%) patients
of the present study, visual acuity impairment or loss was reported.
All of these patients presented with orbital soft tissue involvement
and 2 with documented optical nerve involvement. Bilateral IgG4-
ROD or extra-orbital manifestations were present in only 2 of these
patients and were not predictive of visual impairment. Hence, even
if it has not been considered by the international consensus
statement for the treatment of IgG4-RD as an indication for urgent
treatment, the risk of visual acuity impairment should be a concern
when managing patients with IgG4-ROD.[8]
The association with extra-orbital manifestations was the most
frequent in patients with either LG (100%) or bilateral IgG4-
ROD (100%). This is concordant with previously published data
and further emphasizes the fact that patients with LG or bilateral
IgG4-ROD should be screened for other localizations of the
disease.[6] Besides routine physical and biological evaluations,
there is no consensus on the optimal strategy as for which
radiological investigations to perform, but 18F-FDG PET/CT
could be promising in this setting.[1,8,25]
Biological assessment of patients showed that sIgG4 >1.35 g/L
were found in 58% of patients, which is lower than the rates
5
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reported in previous series (i.e., 63%–100%).[6,16,17] As
previously suggested, sIgG4 elevation was preferentially associ-
ated with bilateral forms, and was associated with extra-orbital
and systemic manifestations of IgG4-RD.[3] Under treatment,
sIgG4 normalized in most evaluable patients (5/6 evaluable
patients treated for IgG4-ROD) and correlated with clinical and
radiological responses of the disease.[26] CRP levels were usually
normal or slightly elevated. Circulating plasmablasts were not
evaluated in these patients as this is not yet performed as routine
biological examination in most centers.[27] Other causes of
orbital inflammation were excluded and ANA were positive only
in a small number of patients, at a low titer and without evidence
of either dsDNA or extractable nuclear antigen (especially SSA or
SSB) autoantibodies.
Pathological analyses of lacrimal gland or orbital soft tissue
biopsies were only available for half of the patients. In the
remaining cases, pathological assessment of IgG4-RD was
performed on extra-orbital tissue biopsies. All patients fulfilled
the “modified” CDC criteria but the pathological consensus
criteria for LG were not fulfilled for all.[7,11] Indeed, a limitation
to the present study was the frequent lack of the IgG4/IgG ratio
measure due to the high background for IgG staining reported by
the pathologists. In some patients, the measure of such a ratio was
performed by analyzing the IgG4/CD138 ratio, which theoreti-
cally can underestimate the IgG4/IgG ratio. Besides, in some
cases, the pathologists did not report on the IgG4 plasma cells
count/HPF despite an increased IgG4/IgG ratio >40%. Fibrosis
was reported in all patients (without storiform pattern otherwise
reported in lacrimal localization of IgG4-RD) except 2 cases
of lacrimal gland and orbital biopsies each. Next, a dense
lymphoplasmacytic infiltrate was reported in all cases. Sparse
eosinophils were observed in only 3 soft tissue biopsies (that did
not comprise LG) and obliterative phlebitis was never reported in
the present series, as previously published in IgG4-ROD.[6,28]
Yet, in all cases, a strict clinicopathologic correlation was
performed to rigorously rule out diseases that mimic IgG4-RD,
especially those presenting with tumefactive lesions and increased
IgG4+ plasma cells on tissue biopsy. Two patients (patients 11
and 12) presented with no extra-orbital manifestations of IgG4-
RD and normal serum IgG4 levels, but were included in order not
to underestimate the true prevalence of IgG4-ROD or even
overlook an entire pattern of patients with strictly localized
orbital disease. After a follow-up period of 19 and 51 months
respectively, no differential diagnosis has appeared in both
patients.
All patients were treated as first-line therapy with prednisone
and clinically improved with such treatment. This high rate of
response to prednisone is a common feature of IgG4-RD.[1,29]
Yet, relapses were frequent (roughly two-thirds of the patients).
This rate is close to the 67% relapse rate reported in a large
international multicentric cohort of AIP.[29] Moreover, 63% of
patients received a second-line therapy, RTX in 9 (47%),
DMARDs (AZA, MMF, or MTX) in 7 (37%), either for a disease
relapse or as a steroid-sparing agent. At last visit, >70% of all
patients remained under treatment with either low-dose predni-
sone, MMF or both, thus highlighting that glucocorticoid-
sparing agents are needed in IgG4-ROD. Definite conclusions
cannot be driven out of this retrospective case series but RTX
seemed highly effective in the present series. Indeed, all but 1
relapsing patients who received RTX as second-line therapy
responded to treatment, and 2 of 3 patients who failed to respond
to a DMARDs second-line therapy were successfully challenged
with RTX as third-line therapy. Overall, DMARDs were poorly
Ebbo et al. Medicine (2017) 96:10
effective and were often withdrawn due to drug-related toxicity.
In 7 cases, RTX was specifically indicated for IgG4-ROD
presenting as: soft tissue (n = 6), EOM (n = 4), nerve (n = 2), or
bone (n = 2) involvements. Of these 7 patients, 2 were off
treatment and 5 remained under maintenance therapy at the last
visit. These results are similar to those previously reported in
other cohorts of patients with IgG4-ROD treated with
RTX.[17,30,31] While RTX indeed seems to be an effective
treatment option for the management of IgG4-RD, the optimal
frequency and duration of infusions remains to be determined.
Moreover, since RTX only seems to have a temporary effect and
that relapses have been reported under treatment, new
therapeutic approaches should be developed. Specifically target-
ing T-cells rather than B-cells could be another approach based
on the characterization of abnormal T-cell subsets in IgG4-RD
and the efficacy reported in a recent case report with a CTLA4-
agonist antibody.[32–34]
Our study has some limitations. First, the French IgG4-RD
case-registry is a declarative registry, thus possibly leading to a
selection bias with the most severe cases reported and milder
presentation of IgG4-ROD possibly underrepresented. Next, our
study has limited sample-size and suffers from the limitations of
its retrospective design, namely missing data (especially patho-
logical findings) and lost to follow-up.
Yet, we report on a well-documented series of patients with
IgG4-ROD with long-term follow-up. Interestingly, clinical and
biological characteristics of IgG4-ROD in this European case-
series are similar to those previously reported in North American
and Asian patients. Lacrimal involvement is the most frequent
manifestation of IgG4-ROD and is frequently associated with
disease-specific extra-orbital manifestations. Despite initial
favorable response to steroids, relapses are frequent and patients
with soft tissue involvement can present with visual impairment.
As second or third-line therapy, RTX was associated with high
remission rates. Yet, the long-term management of relapsing
patients needs to be improved.
Acknowledgments
The authors thank Elisabeth Castanier from the EMAI for data
collection. This work was in part supported by the French
Ministry of Health (Programme Hospitalier de Recherche
Clinique Interregional 2011). The authors also thank the CSL
Behring company France and the ADEREM for their financial
support to set up the National French case-registry for IgG4-RD.
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